Mutation in Bmpr1b leads to optic nerve head dysgenesis and retinal gliosis in mouse.

Neuherberg, Germany A novel N-ethyl-N-nitrosourea (ENU) induced mutation in mice was characterized by irregular forelimb and hindlimb morphology, brachydactyly, irregular cartilage development and alterations in the reproductive system. Additionally, a dramatically enlarged optic nerve head was observed in homozygous mutants. The mutation was mapped by a SNP-based linkage analysis and candidate genes were sequenced. The underlying mutation affects the Bmpr1b gene, particularly by a T->G transversion in the splice donor site of exon 10 leading finally to skipping of exon 10, changing the open reading frame and predicting 26 new amino acids in front of a premature stop codon. Here, we focus on changes during eye development and maturation, since our virtual-drum experiments showed dramatically reduced response to moving stripes in homozygous mutant mice. Bmpr1b is mainly expressed in the lens and in the ventral retina during embryonic and early postnatal stages. In-situ hybridization showed a rather posterior expression area of Pax6 and concomitantly reduced Pax2 expression at homozygous retina at E17.5. It is well known that BMPR1B signals through pSMAD1, 5 and 8. Correspondingly, expression of pSMAD1, 5 and 8 is decreased in E17.5 homozygous mutants, but not at earlier or later stages suggesting that BMPR1B-mediated signaling might act also through other pathways. After birth, expression of GFAP in the optic nerve head increases in the homozygous mutants as compared to the wild-types indicating formation of gliotic changes. In conclusion, we showed that impaired function of Bmpr1b leads to optic nerve head dysplasia and gliosis. Bmp signaling during eye development and the need to examine allelic series will be discussed